Some aspects of the invention relate to compounds, their methods of syntheses, their compositions, and their uses to treat cancer, including but not limited to, breast cancer, kidney cancer, colon cancer, rectal cancer, ovarian cancer, stomach cancer, uterine cancer, carcinoma in situ, and leukemia.
Some research may suggest that pathogenic alterations in endogenous ceramide levels contribute to cancer (e.g., breast cancer) chemoresistance. The bioactive sphingolipid ceramide may be a therapeutic target because it can be involved in the regulation of cellular apoptosis and survival. Several chemotherapeutic agents, including paclitaxol and doxorubicin, can induce apoptosis through induction of ceramide signaling. In fact, decreased synthesis and increased metabolism of the apoptotic sphingolipid ceramide can be a mechanism of chemoresistance in human breast cancer.
Treatment options for cancer can include one or more of surgical intervention, chemotherapy, radiation therapy, and adjuvant systematic therapies. Adjuvants may include but are not limited to chemotherapy, radiation therapy, and endocrine therapies, such as administration of LHRH agonists; antiestrogens, such as tamoxifen; high-dose progestogens; aromatase inhibitors; and/or adrenalectomy.
In recent years, the development of targeted molecular therapeutics has become increasingly based upon the identification of the precise molecular abnormalities that are responsible for malignant progression in human cancers. The identification and molecular characterization of signaling pathways responsible for abnormal growth, inhibition of apoptosis, cellular invasion and metastasis, and angiogenesis have generated some targets for new anticancer drugs. Therapy with tamoxifen and aromatase inhibitors has been a successful targeted therapy for decades. Anthracyclines and taxanes can be (individually or together) part of chemotherapy.
The monoclonal antibody trastuzumab is one example of a targeted therapy for breast cancer. Trastuzumab can be used to treat breast cancers that overproduce a protein called human epidermal growth factor receptor 2 or HER2. This protein is overproduced in about 20% of breast cancers. These HER2-overproducing cancers tend to be more aggressive and are more likely to recur. Trastuzumab targets the HER2 protein, and this antibody, in conjunction with adjuvant chemotherapy, can lower the risk of HER2-overproducing breast cancer recurrence by 50% compared to chemotherapy alone. Clinical trials have demonstrated trastuzumab as an important component of some first-line treatments. In particular, the combination with taxanes and vinorelbine has been established. The addition of trastuzumab to chemotherapy can improve disease-free and overall survival.
Chemotherapy can be used as a single-agent or as a combination, possibly with new targeted therapies where relevant. Resistance to chemotherapeutic agents can be an obstacle to successful management of patients with cancer. Some agents become increasingly ineffective in progressive disease and tumors are then deemed to be drug resistant.
While certain features of this invention shown and described below are pointed out in the claims, the invention is not intended to be limited to the details specified, since a person of ordinary skill in the relevant art will understand that various omissions, modifications, substitutions and changes in the forms and details of the invention illustrated and in its operation may be made without departing in any way from the spirit of the present invention. No feature of the invention is critical or essential unless it is expressly stated as being “critical” or “essential.”